Many therapeutic agents are most effective when made available at a constant rate at or near the absorption site. The absorption of therapeutic agents thus made available generally results in desired plasma concentrations leading to maximum efficacy and minimum toxic side effects. Much effort has been devoted to developing sophisticated drug delivery systems, such as osmotic devices, for oral application. However, there are instances where maintaining a constant blood level of a drug is not desirable. For example, a “position-controlled” drug delivery system (e.g., treatment of colon disease or use of colon as an absorption site for peptide and protein based products) may prove to be more efficacious. A pulsatile delivery system is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms. Ishino et al. disclose a dry-coated tablet form in Chemical Pharm. Bull. Vol. 40 (11), 3036-041 (1992). U.S. Pat. No. 4,851,229 to Magruder et al., U.S. Pat. No. 5,011,692 to Fujioka et al., U.S. Pat. No. 5,017,381 to Maruyama et al., U.S. Pat. No. 5,229,135 to Philippon et al., and U.S. Pat. No. 5,840,329 to Bai disclose preparation of pulsatile release systems. Some other devices are disclosed in U.S. Pat. No. 4,871,549 to Ueda et al. and U.S. Pat. Nos. 5,260,068; 5,260,069; and 5,508,040 to Chen. U.S. Pat. Nos. 5,229,135 and 5,567,441 both to Chen disclose a pulsatile release system consisting of pellets coated with delayed release or water insoluble polymeric membranes incorporating hydrophobic water insoluble agents or enteric polymers to alter membrane permeability. U.S. Pat. No. 5,837,284 to Mehta et al. discloses a dosage form which provides an immediate release dose of methylphenidate upon oral administration, followed by one or more additional doses spread over several hours.
There is a well-established circadian variation in frequency of onset of cardiovascular events including ventricular arrhythmias, stroke, angina, and myocardial infarction. The peak frequency of such events is exhibited in the morning hours, theoretically in conjunction with the morning surge in systolic blood pressure and heart rate. There is also some evidence of a secondary peak in frequency of such events in the late afternoon or evening hours. Although there is some evidence which suggests that long acting propranolol may blunt the circadian variability of sudden cardiac death, it does not appear to attenuate early morning increases in blood pressure observed in hypertensive patients. Thus it would be physiologically advantageous to tailor plasma concentrations of propranolol to the typical circadian patterns of blood pressure and heart rate.
Chronotherapeutics is a means of proportioning plasma drug concentrations during a 24-hour period, relative to the biological rhythm determinates of disease activity. The objective of chronotherapy is to deliver the drug in higher concentrations during the time of greatest need, and in lesser concentrations when the need is less. The dosage forms disclosed in the prior arts above are not specifically designed to provide drug release profiles varying predictably in time over 24 hours, i.e., in a circadian rhythm fashion to effectively treat cardiovascular diseases. The dosage forms of the present invention, Propranolol Hydrochloride ER Capsules, 80, 120, and 160 mg), which are typically administered at bedtime, i.e., at about 10:00 PM, are novel formulations designed to provide reductions in blood pressure and heart rate over 24 hours, including optimal protection in the early morning hours when patients are most vulnerable to cardiovascular events. At steady state, blood levels of propranolol begin to increase approximately 4 hours after bedtime administration of these capsules and rise progressively over the early morning hours to reach peak plasma concentrations approximately 14 hours after dosing. These capsules produce peak plasma propranolol levels that rise slowly to attenuate the rapid increase in blood pressure and heart rate that precedes and follows waking. This increase is associated with circadian variation in catecholamine secretion and in rennin release. The rise in plasma propranolol concentration after dosing with these capsules parallel the circadian rise in morning blood pressure associated with target organ damage in patients with hypertensive and ischemic cardiovascular disease.
Propranolol [1-(isopropyl amino)-3-(1-naphthyloxy)-2-propanol] is a beta-adrenergic blocking agent and as such is a competitive inhibitor of the effects of catecholamines at beta-adrenergic receptor sites. The principal effect of propranolol is to reduce cardiac activity by diminishing or preventing beta-adrenergic stimulation. By reducing the rate and force of contraction of the heart, and decreasing the rate of conduction of impulses through the conducting system, the response of the heart to stress and exercise is reduced. These properties are used in the treatment of angina in an effort to reduce the oxygen consumption and increase the exercise tolerance of the heart. Propranolol is also used in the treatment of cardiac arrhythmias to block adrenergic stimulation of cardiac pacemaker potentials. Propranolol is also beneficial in the long term treatment of hypertension. Other uses of propranolol are in the treatment of migraine and anxiety.